title: ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension.
abstract: Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190+/-4 versus 152+/-2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49+/-4% versus 81+/-4%, P<.0001) and contractions to ET-1 (92+/-7 versus 136+/-8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168+/-3 versus 190+/-4 mm Hg, P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ET(A) receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.
authors.affiliation: Cardiology, University Hospital Zürich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Barton
authors.forename: L V
authors.initials: LV
authors.lastname: d'Uscio
authors.forename: S
authors.initials: S
authors.lastname: Shaw
authors.forename: P
authors.initials: P
authors.lastname: Meyer
authors.forename: P
authors.initials: P
authors.lastname: Moreau
authors.forename: T F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D006984:Hypertrophy; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009599:Nitroprusside / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D044022:Receptor, Endothelin A; D012982:Sodium, Dietary; D013599:Systole / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D012982:Sodium, Dietary; D009599:Nitroprusside; C107831:darusentan; D011189:Potassium Chloride; D000109:Acetylcholine